Purinergic (P2X) receptors are ATP-gated cation—selective channels. Each receptor is made up of three protein subunits or monomers. To date seven separate genes encoding P2X monomers have been identified: P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, P2X7.
P2X7 receptors are of particular interest as the expression of these receptors is understood to be limited to cells having potential to undergo programmed cell death, such as thymocytes, dendritic cells, lymphocytes, macrophages and monocytes. There is some expression of P2X7 receptors in normal homeostasis, such as on erythrocytes and in other cell types such as skin at generally lower levels.
Interestingly, a P2X7 receptor containing a monomer having a cis isomerisation at Pro210 (according to SEQ ID NO: 1) and which has compromised ATP binding function at the affected site or sites has been found on cells that are understood to be unable to undergo programmed cell death, such as pre-neoplastic cells and neoplastic cells. This isoform of the receptor has been referred to as a “non-functional” receptor and describes a form of the receptor unable to extend the operating non-selective calcium channel into an apoptotic pore.
Antibodies generated from immunisation with a peptide including Pro210 bind to non-functional P2X7 receptors at the altered ATP binding site/s formed between adjacent monomers. However, they do not bind to P2X7 receptors capable of binding ATP at any of the three available sites. Accordingly, these antibodies are useful for selectively detecting many forms of carcinoma and haemopoietic cancers and to treatment of some of these conditions.
WO02/057306A1 and WO03/020762A1 discuss a probe in the form of a monoclonal antibody for distinguishing between functional P2X7 receptors, defined as those receptors able to form a non-selective Ca/Na channel that is additionally able to form an apoptotic pore upon extended binding of ATP, and non-functional P2X7 receptors, defined as those receptors able to form the non-selective channel but that are unable to extend opening of the channel to an apoptotic pore.
WO2009/033233 discusses an epitope exposed on non-functional receptors but not functional receptors and antibodies for binding thereto.
There exists a need for an alternative or improved treatment of diseases caused by or associated with non-functional P2X7 receptor expression, such as cancer.
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